Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality, Ventricular Dilatation and Deranged Matrix during Cardiac Pressure Overload

RationaleInflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. ObjectiveWe sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. Methods and ResultsMice harboring a systemic knockout of the CXCR5 (CXCR5−/−) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5−/− developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5−/− compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5−/− mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. ConclusionsLack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly.研究背景：已有研究提示炎症机制参与心力衰竭（heart failure, HF）的发生发展，但趋化因子在其中的作用目前仍不明确。鉴于趋化因子在其他组织的炎症反应与基质重塑过程中发挥的作用，我们提出假设：趋化因子C-X-C基序配体13（CXCL13）及其受体C-X-C基序受体5（CXCR5）可能参与心力衰竭进程中的心肌重构。研究目的：本研究旨在分析CXCL13与CXCR5在导致心力衰竭的心脏病理生理过程中的作用。方法与结果：系统性敲除CXCR5的小鼠（CXCR5−/−）在主动脉结扎（aortic banding, AB）术后80天的随访周期内，死亡率显著升高。主动脉结扎术后三周，CXCR5基因敲除小鼠相较于野生型（wild type, WT）小鼠，出现了显著的左心室（left ventricular, LV）扩张。基因芯片分析结果显示，多种可结合胶原蛋白并调节胶原纤维组装的富含亮氨酸重复序列小分子蛋白聚糖（small leucine-rich proteoglycans, SLRPs）的表达水平发生改变。与接受主动脉结扎的野生型小鼠相比，主动脉结扎后的CXCR5基因敲除小鼠体内，纤调蛋白（fibromodulin）、饰胶蛋白（decorin）及闪光蛋白（lumican，三者均属于SLRPs）的蛋白水平显著降低。电子显微镜观察显示，主动脉结扎后的CXCR5基因敲除小鼠的细胞外基质排列松散，可见独立的胶原纤维与小型蛋白聚糖网络。向体外培养的心肌成纤维细胞中添加CXCL13，可上调SLRPs的表达。在心力衰竭患者中，我们观察到心肌组织内CXCR5与SLRPs的水平升高，而左心室辅助装置（left ventricular assist device, LVAD）治疗可逆转该现象。结论：在压力超负荷状态下，CXCR5的缺失会导致左心室扩张并升高死亡率，这一过程可能与SLRPs的表达无法出现上调有关。本研究证实，CXCL13与CXCR5可通过调节胶原蛋白正确组装所必需的蛋白聚糖，在压力超负荷状态下对机体存活与心脏结构维持发挥关键作用。